Candida albicans, the primary causative agent of fungal vaginitis, will affect 75% of all women of reproductive age at least once in their lifetime. Long believed to result from immunodeficiency, a growing body of evidence strongly suggests that vaginitis is now considered to be an immunopathology, in which the host response actually drives disease symptoms. Lack of a comprehensive understanding of the host and fungal factors that initiate symptomatic disease remains a barrier to progress in better treating and managing this most prevalent human candidal infection. Despite being associated with vaginitis onset, the role for neutrophils in driving disease symptoms remain unclear, partly complicated by current animals that do not reflect disease symptomatology. Guided by strong published and preliminary data, we have now developed a mouse model of infection that results in classical vaginitis symptoms (redness, swelling, itching of the vaginal mucosa). Therefore, the objectives of this proposal is to determine if Candidalysin and/or host neutrophils are required for symptomatic vaginitis and to identify how host genetic variation sensitizes to symptomatic disease. These aims will test our central hypothesis that Candidalysin is required, while neutrophils are dispensable, for symptomatic infection. Under the first aim, we will use fungal strains deleted for Candidalysin and neutrophil depletion strategies to determine requirements of these factors for driving disease symptomatology observed in DBA/2 mice. The second aim will utilize a reference panel of recombinant inbred mouse strains (BXDs) and downstream phenotypic and statistical analyses to identify quantitative trait loci (QTLs) associated with symptomatic infection. Follow up studies using gene expression and knockdown approaches will validate these findings. The outcomes of this project will provide foundational information regarding the immunopathogenesis of vulvovaginal candidiasis and may shift the current paradigm of the neutrophil-centric model. We also aim to identify alleles associated with symptomatic disease that can be interrogated at the human population level in a future clinical study.